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Exon 3 β-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome

机译：外显子3β-catenin突变与遗传性非息肉病性大肠癌综合征中的大肠癌特异性相关

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>Background and aim: Activating β-catenin mutations in exon 3 have been implicated in colorectal tumorigenesis. Although reports to the contrary exist, it has been suggested that β-catenin mutations occur more often in microsatellite unstable (MSI+) colorectal carcinomas, including hereditary non-polyposis colorectal cancer (HNPCC), as a consequence of defective DNA mismatch repair. We have analysed 337 colorectal carcinomas and adenomas, from both sporadic cases and HNPCC families, to provide an accurate assessment of β-catenin mutation frequency in each tumour type.>Methods: Direct sequencing of exon 3 of β-catenin.>Results: Mutations were rare in sporadic (1/83, 1.2%) and HNPCC adenomas (1/37, 2.7%). Most of the sporadic adenomas analysed (80%) were small (<1 cm), and our data therefore differ from a previous report of a much higher mutation frequency in small adenomas. No oncogenic β-catenin mutations were identified in 34 MSI+ and 78 microsatellite stable (MSI−) sporadic colorectal cancers but a raised mutation frequency (8/44, 18.2%) was found in HNPCC cancers; this frequency was significantly higher than that in HNPCC adenomas (p = 0.035) and in both MSI− (p<0.0001) and MSI+ (p = 0.008) sporadic cancers. Mutations were more common in higher stage (Dukes’ stages C and D) cancers (p = 0.001).>Conclusion: Exon 3 β-catenin mutations are associated specifically with malignant colorectal tumours in HNPCC; mutations appear not to result directly from deficient mismatch repair. Our data provide evidence that the genetic pathways of sporadic MSI+ and HNPCC cancers may be divergent, and indicate that mutations in the HNPCC pathway of colorectal tumorigenesis may be determined by selection, not simply by hypermutation.
机译：>背景和目标：外显子3中活化的β-catenin突变与结直肠肿瘤的发生有关。尽管有相反的报道，但有人提出，由于DNA错配修复缺陷，β-catenin突变在微卫星不稳定（MSI +）结直肠癌（包括遗传性非息肉病结直肠癌（HNPCC））中更常见。我们分析了散发病例和H​​NPCC家族的337例大肠癌和腺瘤，以准确评估每种肿瘤类型中β-catenin突变的频率。>方法：β-外显子3的直接测序>结果：散发性突变（1 / 83，1.2％）和HNPCC腺瘤（1 / 37，2.7％）很少见。分析的大多数散发性腺瘤（80％）很小（<1 cm），因此我们的数据不同于先前报道的小腺瘤突变频率更高的报道。在34例MSI +和78例微卫星稳定（MSI-）散发性结直肠癌中未发现致癌的β-catenin突变，但在HNPCC癌中发现了升高的突变频率（8/44，18.2％）。该频率明显高于HNPCC腺瘤（p = 0.035）和MSI-（p <0.0001）和MSI +（p = 0.008）散发性癌症。突变在晚期（杜克大学的C和D期）癌症中更为常见（p = 0.001）。>结论：外显子3β-catenin突变与HNPCC的大肠直肠癌特别相关；突变似乎不是由于错配修复不足直接导致的。我们的数据提供了证据，表明散发性MSI +和HNPCC癌症的遗传途径可能不同，并表明大肠肿瘤发生的HNPCC途径中的突变可能是通过选择确定的，而不仅仅是通过高突变。

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